(a) Field of Invention
This invention relates to novel 1-azabicyclo[2.2.2]octan-3-yl 2-aryl-3-azacyclo-2-hydroxypropionates and their quaternary salts and their use as antimuscarinic agents having antisecretory activity selective for the gastrointestinal tract.
(b) State of the Art
Blockade of the action of acetylcholine at muscarinic cholinergic receptors in various tissues produces antispasmodic, antisecretory and mydriatic effects. As a result, such compounds have a broad range of therapeutic applications, notably as antispasmodics, as an adjunct in the management of peptic ulcer, as adjuvants in the management of functional disorders of the bowel, such as irritable colon, spastic colitis, ulcerative colitis, diverticulitis, and irritable bowel syndrome.
Unfortunately, many of these agents lack specificity; that is, they produce side effects, notably, central nervous system symptoms such as dizziness and hallucinations [B. V. Rama Sastry, in "Burger's Medicinal Chemistry", Edited by M. E. Wolff, 4th Edition, Part III, Wiley-Interscience, New York, 1980, pp. 361-411; S. N. Pradhan, in "Pharmacology in Medicine: Principles and Practice", Edited by S. N. Pradhan, R. P. Maickel and S. N. Dutta, SP Press, Bethesda, Md., 1986, pp. 138-165)].
The novel 1-azabicyclo[2.2.2]octan-3-yl 2-aryl-3-azacyclo-2-hydroxypropionates and their quaternary salts described herein are potent antimuscarinic agents with a high degree of selectivity for the gastrointestinal tract as evidenced by their ability to displace muscarinic ([.sup.3 H]QNB) ligands from their tissue binding sites, decrease colonic motility and to inhibit carbachol-induced diarrhea in animals. The polar nature of these compound limits their access to the central nervous system. These actions indicate usefulness of these substances as antispasmodics and in the treatment of irritable bowel syndrome.